Total Parenteral nutrition (TPN) provides nutrition by bypassing the gut. It is a crucial lifesaving therapy for over 30,000 individuals in the US permanently dependent on TPN. Several fold higher number of patients require TPN for a prolonged duration. It is also used worldwide. Unfortunately, its use causes potentially fatal live and gut injury from a likely multifactorial, yet unknown etiology. No established ameliorative strategies exist. Dr. Jain is a board certified pediatric gastroenterologist and a tenure track Assistant Professor at Saint Louis University (SLU). His long term career goal is to become an independent NIH-funded physician scientist in the niche field to develop strategies to ameliorate TPN associated pathology. His focus is on understanding the interplay of bile acid regulated pathways that modulate the Gut-Liver axis during TPN infusion. The objective of the current K08 proposal is to obtain training in designing hypothesis driven proposals, acquiring research techniques, performing experiments, critically analyzing data and developing skills to overcome pitfalls. With this award he will be able to generate a critical mass of data and publications to support a successful NIH R01 grant application. With his mentors he has successfully setup an advanced ambulatory TPN model at SLU. He has obtained very encouraging new data resulting in publications, funded by competitive University grants and recently via extramural funds from the NASPGHAN young investigator award and the ASPEN Rhoads research award. He has presented his findings at several national meetings including premier paper sessions. As detailed in his research plan; with Aim 1 he will evaluate gut and hepatic outcomes in TPN infused animals given Farnesoid X Receptor (FXR) agonists and the FXR regulated downstream protein FGF19 to determine mechanistic links. Aim 2 relates to exploring the mechanisms by which the TGR5-GLP axis additionally regulates TPN pathology. He will test responses to intravenously infused Glucagon Like Peptides 1 & 2 and enterally administered TGR5 agonist in animals receiving TPN. Aim 3 addresses alteration in gut microbiota, specifically a clonal Bacteroidetes proliferation leading to impaired gut integrity and thus endotoxin and cytokine mediated injury in animals on TPN. Each of his aims uses several highly novel strategies. These aims support Dr. Jain's career development by providing training in mechanistic aspects of TPN pathobiology as related to the roles of bile acid regulated pathways. Additional key elements of Dr. Jain's training plan include: 1) A mentorship and advisory team, which includes internationally recognized, independently funded investigators. 2) Advanced and exhaustive coursework. 3) `Hand on' regular monitoring of progress with achievable goals and targets. Finally, Dr. Jain has a research environment in a preeminent academic research institution (Saint Louis University) with leaders in the field at the SLU Liver center, a designate center of excellence. However, most importantly, Dr. Jain is a candidate who has shown extreme determination to advance his research and has full institutional commitment to enable him succeed.